Gestational autoantibody exposure impacts early brain development in a rat model of MAR autism

Abstract

Maternal autoantibody-related autism (MARA) is a subtype of autism characterized by the maternal production of specific patterns of autoantibodies during pregnancy, which significantly increases the likelihood of an autism diagnosis in their children. Multiple patterns of MARA autoantibodies (MARA-ABS) have been identified, and differences in the severity of the autism phenotype associated with each autoantibody pattern have been described. In this study, we utilized preclinical rat models to further elucidate the differential effects of MARA-AB exposure based on the known clinical patterns, including the originally reported pattern of lactate dehydrogenase A and B (LDHA/B) + collapsin response mediator protein 1 (CRMP1) + stress-induced phosphoprotein 1 (STIP1), as well as the more recently described patterns of CRMP1+CRMP2, CRMP1 + guanine deaminase (GDA), and STIP1+ neuron-specific enolase (NSE). We induced endogenous MARA-AB production in rat dams before pregnancy to expose offspring to the ABs throughout gestation. We found that in postnatal day 2 offspring exposed to MARA-ABS, the levels of brain and serum cytokines/chemokines/growth factors were altered based on the pattern of MARA-AB exposure. Further, bulk transcriptomic profiles of coronal sections containing hippocampal formation and the adjacent cortical and subcortical structures suggested changes in cellular proliferation and differentiation following MARA exposure. These combined observations demonstrate that gestational exposure to MARA-ABS alters early gene expression and immune signaling molecules, both of which may contribute to the altered neurodevelopment and behaviors associated with MARA.

Fig. 1. MAR rat model creation.

a Timeline of autoantibody generation in naïve female rat dams and subsequent allocation of offspring. b Average optical densities of rat dams at baseline and after receiving immunizations.

Fig. 2. Effect size comparisons between LDHA/B+CRM1+STIP1-exposed and control offspring.

Estimated effect sizes (Cohen’s d) for adjusted group differences between LDHA/B+CRMP1+STIP1 and control groups in PND2 offspring brain (a) and sera (b) cytokine, chemokine and growth factor concentrations were assessed using linear mixed-effects models. Cytokine, chemokine, and growth factors with higher concentrations in offspring from treated dams than controls are shown in yellow. Those with higher concentrations in offspring from control dams than those from treated dams are shown in blue. Comparisons with significant group differences (p < 0.05) are marked with asterisks (*).

Fig. 3. Effect size comparisons between CRMP1+CRMP2, STIP1+NSE, and CRMP1+GDA-exposed offspring.

Estimated effect sizes (Cohen’s d) for adjusted pairwise group differences between CRMP1+CRMP2, STIP1+NSE, and CRMP1+GDA groups in PND2 offspring brain (a) and sera (b) cytokine, chemokine, and growth factor concentrations assessed using mixed-effects linear models. Cytokine/chemokines/growth factors with higher concentrations in offspring from CRMP1+CRMP2 dams compared to offspring from STIP1+NSE or CRMP1+GDA dams are shown in green. Those with higher concentrations in offspring from CRMP1+GDA dams are shown in blue. Those with higher concentrations in offspring STIP1+NSE dams are shown in yellow. Comparisons with significant group differences (p < 0.05) are marked with asterisks (*).

Fig. 4. General MARA DE signature.

a Number of DE genes passing thresholds of p < 0.05 and FDR < 01. b Upregulated genes across DE models passing FDR < 0.1. c Downregulated genes across DE models passing FDR < 0.1 (d) GO enrichment of top up- and downregulated genes across all DE models passing FDR < 0.1.

Fig. 5. DE analysis by autoantibody exposure.

a Numbers of DE genes passing thresholds of p < 0.05 and FDR < 01. b Volcano plots split by autoantibody exposure. c Intersections of 100 most significant DE genes by autoantibody exposure. d Correlations of top 100 DE genes log2 fold changes. e CRMP1+CRMP2 GO enrichment for up- and downregulated genes passing FDR < 0.1.